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Background: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC., Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab., Conclusions: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time., Competing Interests: Competing interests JMS, AON, TJS, WJG, EAP, and ACW have no conflicts of interest related to this project. CLA has served as scientific advisor to Novartis, Lilly, Merck, Immunomedics, Daiichi Sankyo, AstraZeneca, PUMA Biotechnology, TAIHO Oncology, OrigiMed, Arvinas, Sanofi, and the Susan G. Komen Foundation. He has received grant support from Pfizer, Lilly, and Takeda. NJM is an employee of Flatiron Health, Inc. an independent member of the Roche group, and reports stock ownership in Roche. VGA has served as a scientific advisor for GuardantHealth and Astra Zeneca and has research funding support from Genetech, Bayer, and GuardantHealth. NUL declares consulting honorarium from Seagen, Daichii-Sankyo, AstraZeneca, Olema Pharmaceuticals, Janssen, Blueprint Medicines, Stemline/Menarini, Artera Inc., Eisai; travel support from Olema Pharmaceuticals; research support (to institution) from Genentech, Zion Pharmaceuticals (as part of GNE), Pfizer, Seagen, Merck, Olema Pharmaceuticals, AstraZeneca; royalties from Up To Date. SAR has served as a consultant for Daiichi-Sankyo, Astra Zeneca, Novartis, and Gilead.